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Thursday, 9 June 2016

Atkins, ketones, methylglyoxal and cancer

What you lose on the swings you make up for on the roundabouts.

Recently this study enjoyed a bit a revival as it was used in a presentation at a DAA meet. I'm not sure of the exact context but the Dietitians Association of Australia has been outstandingly fossilised in its attitude to low carb diets.

Ann N Y Acad Sci. 2005 Jun;1043:201-10.

Ketosis leads to increased methylglyoxal production on the Atkins diet.
Beisswenger BG, Delucia EM, Lapoint N, Sanford RJ, Beisswenger PJ.

In the popular and widely used Atkins diet, the body burns fat as its main fuel. This process produces ketosis and hence increased levels of beta-hydroxybutyrate (BOB) acetoacetate (AcAc) and its by-products acetone and acetol. These products are potential precursors of the glycotoxin methylglyoxal. Since methylglyoxal and its byproducts are recognized as a significant cause of blood vessel and tissue damage, we measured methylglyoxal, acetone, and acetol in subjects on the Atkins diet. We found that by 14-28 days, methylghyoxal levels rose 1.67-fold (P = 0.039) and acetol and acetone levels increased 2.7- and 6.12-fold, respectively (P = 0.012 and 0.028). Samples from subjects with ketosis showed even greater increases in methylglyoxal (2.12-fold), as well as acetol and acetone, which increased 4.19- and 7.9-fold, respectively; while no changes were seen in samples from noncompliant, nonketotic subjects. The increase in methylglyoxal implies that potential tissue and vascular damage can occur on the Atkins diet and should be considered when choosing a weight-loss program.

Glycation is the major cause of neurological, optic, tissue and vascular damage in diabetes. Glucose, fructose, and methylglyoxal are precursors of advanced glycation endproducts (AGEs). Glycation of proteins creates free-radical generating hotspots. Amongst other things, almost all bad, this does at least serve the function of keeping further excess substrate out of cells.

"Glycation has the potential to alter the biological structure and function of the serum albumin protein. Once it is glycated, it is less efficient for carrying long chain fatty acid.

In experimental model of adipocyte cell lines, albumin-derived AGE has been shown to trigger the generation of intracellular reactive oxygen species leading to an inhibition of glucose uptake."
Chris Masterjohn has written at length about methylglyoxal pathways here. Suffice to say that there are pathways to clear methylglyoxal, and that the effects of glycation, shown by elevated HbA1c, neuropathy, and microvascular complications have never so far as I know been reported in persons on ketogenic diets. That is, HbA1c in type 2 diabetics drops sharply on a ketogenic diet, but can rise in non-diabetics, though only within the normal range.

One reason for thinking that ketogenic diets are healthy is the Warburg effect. Otto Warburg won the Nobel Prize in 1931 for "discovery of the nature and mode of action of the respiratory enzyme". In 1924 he postulated the Warburg theory of cancer, which (according to Wikipedia) "postulates that the driver of tumorigenesis is an insufficient cellular respiration caused by insult to mitochondria. The term Warburg effect describes the observation that cancer cells, and many cells grown in-vitro, exhibit glucose fermentation even when enough oxygen is present to properly respire. In other words, instead of fully respiring in the presence of adequate oxygen, cancer cells ferment. The Warburg hypothesis was that the Warburg effect was the root cause of cancer. The current popular opinion is that cancer cells ferment glucose while keeping up the same level of respiration that was present before the process of carcinogenesis, and thus the Warburg effect would be defined as the observation that cancer cells exhibit glycolysis with lactate secretion and mitochondrial respiration even in the presence of oxygen."

The ketogenic diet is proposed, and used, as a cancer therapy because it limits exposure to glucose and fructose, which cancer cells can use via the Warbug (and reverse Warburg) effect, and replaces a large part (up to half) of the glucose requirement with ketone bodies, which most tumours cannot easily use.
But what about methylglyoxal? Can cancer cells use methylglyoxal?

No. Methylglyoxal is cytotoxic, without being much of an energy substrate.
A novel mechanism of methylglyoxal cytotoxicity in prostate cancer cells. Link
 Antognelli C, Mezzasomaa L, Fettucciari K, Talesa VN.
The International Journal of Biochemistry & Cell Biology

Volume 45, Issue 4, April 2013, Pages 836–844The results suggest that this physiological compound merits investigation as a potential chemo-preventive/-therapeutic agent, in differently aggressive prostate cancers.

Here's a summary of methylglyoxal cancer research, which includes a human trial. The trial report is linked here.

Do levels of methylglyoxal on a ketogenic diet equal those used in the trial? Probably not. But a ketogenic diet both removes much of the glycolytic fuel that cancers prefer, and replaces it with ketones which they (mostly) can't use, and which is liable to turn into methylglyoxal, which is deadly poison to them.

A useful way of looking at these things is to compare cancer risk in type 1 and type 2 diabetes. Both are exposed to similar levels of excess glucose, but people with type 1 diabetes are occasionally exposed to higher ketone, and thus methylglyoxal, levels (I'm talking about the usual loose management of these conditions, not people on low carb diets).
"It turns out that the types of cancer that are elevated among type 1 diabetes patients are pretty much the same as those that are elevated among type 2 diabetes patients, and the elevation among type 1 diabetes patients is somewhat smaller than the elevation found among type 2 diabetes patients." Link

A ketogenic diet is great for making people metabolically healthy. I don't see why this would result in greater longevity compared to other people who are metabolically healthy. It's a way of catching up, not necessarily of racing ahead.


Passthecream said...

Nicely put. Whenever I need to feel that I'm not just racing to keep up, I reassure myself with the thought that if I was metabolically better endowed then I might be a bit better off with what I'm attempting than those who take their health for granted!

'The current popular opinion is that cancer cells ferment glucose while keeping up the same level of respiration'

I'm slowly working my way through this paper atm but there are a few interesting points along those lines:

Interesting that whilst metformin has a reputation as a 'mitocan' these authors relate that it doesn't seem to cause any changes at complex I vs rottenone which is overwhelming and the combination of both is potent for initiating apoptosis. Their earlier paper 'the good the bad and the ugly about oxidative stress' is interesting also.

Michael said...

Greetings! I have started a Facebook discussion page further to my own (humble) research and would like you to know about it. Your page is wonderful. I feel that methylglyoxal is being unnecessarily maligned. I am in the process of researching a paper on the subject, analyzing how, perhaps, one single paper in the 80s may have created a negative aura around the use of methylglyoxal as a treatment for cancer. I have seen several references to Szent-Gyorgi's interest in this topic having been founded in his observation of the ANTI-VIRAL properties of methylglyoxal. You have an excellent site and I'm so pleased to read you and learn from you.
Michael in Toronto, Canada

Michael said...

George Henderson said...

Thanks Michael - joined up, will post when I have more time.

erdoke said...

"conclusions about the potential beneficial effects of methylglyoxal have often been neglected, thus hindering the advancement of medical science and causing some confusion in fundamental understanding. Overall, the potential beneficial effects of methylglyoxal far outweigh its possible toxic role in vivo"